Neurotrophic difluoroamide agents

ABSTRACT

The present invention relates to the design, synthesis, and the peptidyl-prolyl isomerase (PPIase or rotamase) inhibitory activity of novel α,α-difluoroacetamido compounds that are neurotrophic agents (i.e. compounds capable of stimulating growth or proliferation of nervous tissue) and that bind to immunophilins such as FKBP12 and inhibit their rotamase activity. This invention also relates to pharmaceutical compositions comprising these compounds.

This application is based on provisional application No. 60/087,642filed Jun. 2, 1998.

BACKGROUND OF THE INVENTION

Immunophilins are cytosolic proteins endowed withpeptidylprolyl-cis-trans isomerase (PPIase or rotamase) activity. Thisfamily of proteins behave as chaperone molecules causing cis-transisomerization of specific prolyl amide bonds that could be a ratelimiting step in the correct folding of certain proteins. They are alsoinvolved in many cellular signal transduction pathways as partners inmultiprotein complexes for which binding in the rotamase active site,but not rotamase activity per se, appears to be important (Ruhlmann, etal., Immunobiol., 198, pp. 192-206 (1998)). Immunosuppressive drugs suchas FK506, rapamycin and cyclosporin A bind to specific groups ofimmunophilins. FK506 and rapamycin bind to the so-called FK506-bindingproteins (e.g. FKBP-12, -25, -52), whereas the cyclophilins bind tocyclosporin A. It has been shown that binding to the 12kD immunophilinFKBP12 is necessary for FK506 to elicit its immunosuppressive activity.Subsequently, it was also found that FK506 has two binding domains: onethat binds to FKBP12 and the other (the effector domain) for the complexof FK506 and FKBP12 that binds to the serine/threonine phosphatase,calcineurin. This complexation inhibits calcineurin and prevents theproliferation of T-lymphocytes, causing immunosuppression. Rapamycin hasan effector domain of a different structure, and its complex with FKBP12binds to a different target protein that, however, has the same effectof inhibiting T-lymphocyte proliferation. For a review, see S. L.Schreiber, et al., Tetrahedron, 48, pp. 2545-2558 (1992).

While FK506 exhibits immunosuppressive effects, analogs lacking thecalcineurin binding effector domain are devoid of immunosuppressiveactivity. Many small molecules that contain the essential elements ofthe FKBP12 binding domain of FK506 but lack the calcineurin bindingdomain were found to retain high affinity binding to FKBP12, and behaveas rotamase inhibitors (D. S. Yamshita, et al., Bioorg. Med. Chem.Lett., 4, pp. 325-328 (1994); D. M. Armistead, et al., Acta Cryst. D,51, pp. 522-528 (1995)).

FK506 has been shown to possess neurotrophic properties in vitro and invivo (W. E. Lyons, et al., Proc. Natl. Acad. Sci USA, 91, pp. 3191-3195(1994); B. G. Gold, et al., J. Neurosci., 15, pp. 7509-7516 (1995)).However, its immunosuppressive properties as well as other serious sideeffects are drawbacks to its use as a neuroregenerative agent. Recently,in vitro studies in PC12 cells, SY5Y cells, and chick sensory dorsalroot ganglion explant cultures have shown that small molecule,nonimmunosuppressive FKBP12 rotamase inhibitors also promote neuriteoutgrowth, and a number of these compounds have shown utility inreversal of CNS lesioning and nerve crush in animal models (G. S.Hamilton, et al., Curr. Pharm. Design, 3, pp. 405-428 (1997); B. G.Gold, et al., Exp. Neurol., 147, pp. 269-278 (1997)). Thus, while thecalceineurin binding domain of FK506 is necessary for immunosuppressiveactivity, it is not required for neurotrophic activity.

A 10-50 fold elevated expression of immunophilins in the central nervoussystem in comparison with the immune system is well documented (S. H.Snyder, et al., Nature Med., 1, pp. 32-37 (1995)). Recently, augmentedexpression of FKBP12 m-RNA following facial nerve crush and sciaticnerve lesions was established in facial and lumbar motor neurons. Theobserved augmentation paralleled the enhanced expression of growthassociated protein GAP43 mRNA (B. G. Gold, et al., Neurosci. Lett., 241,pp. 25-28 (1998)). These observations make FKBP12 an attractive targetfor developing nonimmunosuppressive rotamase inhibitors which promoteneurite outgrowth. Such compounds are potential therapeutics to reverseneuronal damage caused by neurodegenerative disease or physical trauma.

There have been disclosures of related compounds for overcomingmultidrug resistance (MDR) or as immunosuppressants such as:

WO 94/07858 published Apr. 14, 1994 WO 92/19593 published Nov. 12, 1992U.S. Pat. No. 5,622,970 granted Apr. 22, 1997 U.S. Pat. No. 5,330,993granted Jul. 19, 1994 U.S. Pat. No. 5,192,773 granted Mar. 9, 1993 U.S.Pat. No. 5,516,797 granted May 14, 1996 WO 92/21313 published Dec. 10,1992 European Application 564924 published Oct. 13, 1993 EuropeanApplication 405994 published Jan. 2, 1991

Other prior art disclosing related compounds having neurotrophicactivity are:

WO 96/40140 published Dec. 19, 1996 WO 96/40633 published Dec. 19, 1996WO 97/16190 published May 9, 1997 WO 96/41609 published Dec. 27, 1997U.S. Pat. No. 5,696,135 granted Dec. 9, 1997 WO 97/36869 published Oct.9, 1997 U.S. Pat. No. 5,721,256 granted Feb. 24, 1998 U.S. Pat. No.5,654,332 granted Aug. 5, 1997 WO 98/13343 published Apr. 2, 1998 WO98/13355 published Apr. 2, 1998

Since there are relatively few FKBP12-binding compounds that are knownto stimulate neurite growth, there remains a great need for additionalneurotrophic, FKBP12-binding compounds.

SUMMARY AND OF THE INVENTION

Surprisingly, applicant has solved the aforementioned problem. Thepresent invention relates to novel α,α-difluoro substituted acetamidecompounds and pharmaceutical compositions thereof that possessneurotrophic properties.

DETAILED DESCRIPTION OF THE INVENTION

According to one embodiment, the present invention provides:

A compound with affinity for an FK506 binding protein having the formula(I): ##STR1## and pharmaceutically acceptable salts thereof: wherein Wis CH₂, O, NH, or N--(C₁ -C₄)-alkyl;

wherein J is hydrogen, (C₁ -C₄)-alkyl or benzyl;

wherein K is (C₁ -C₄)-straight or branched alkyl, benzyl orcyclohexylmethyl, or wherein J and K may be taken together to form a 5-7membered heterocyclic ring which may contain a heteroatom selected fromthe group consisting of O, S, SO, and SO₂ ;

wherein the stereochemistry at carbon position 1 is R or S;

wherein Z is Q or --(CH₂)_(m) --C(H)Q'A;

wherein m is 0-3;

wherein Q is hydrogen, CHL-Ar, (C₁ -C₆)-straight or branched alkyl, (C₂-C₆)-straight or branched alkenyl, (C₅ -C₇)-cycloalkyl, (C₅-C₇)-cycloalkenyl, Ar substituted (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or##STR2## wherein L and G are independently hydrogen, (C₁ -C₆)-straightor branched alkyl, (C₂ -C₆)-straight or branched alkenyl;

wherein T is Ar or substituted cyclohexyl with substituents at positions3 and 4 which are independently selected from the group consisting ofhydrogen, hydroxyl, O--(C₁ -C₄)-alkyl or O--(C₂ -C₄)-alkenyl andcarbonyl;

wherein D is (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight orbranched alkenyl, (C₅ -C₇)-cycloalkyl or (C₅ -C₇)-cycloalkenylsubstituted with (C₁ -C₄)-straight or branched alkyl or (C₂-C₄)-straight or branched alkenyl, O--(C₁ -C₄)-straight or branchedalkyl, O--(C₂ -C₄)-straight or branched alkenyl, 2-indolyl, 3-indolyl,[(C₁ -C₄)-alkyl or (C₂ -C₄)-alkenyl]-Ar or Ar;

wherein Ar is a carbocyclic aromatic group selected from the groupconsisiting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl,fluorenyl, and anthracenyl; or a heterocyclic aromatic group selectedfrom the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl,isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl,1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, and phenoxazinyl;

wherein Ar may contain one to three substituents which are independentlyselected from the group consisting of hydrogen, halogen, hydroxyl,hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl,O--[(C₁ -C₄)-straight or branched alkyl], O-benzyl, O-phenyl,1,2-methylenedioxy, amino, carboxyl, N-[(C₁ -C₅)-straight or branchedalkyl or (C₂ -C₅)-straight or branched alkenyl] carboxamides,N,N-di-[(C₁ -C₅)-straight or branched alkyl or (C₂ -C₅)-straight orbranched alkenyl] carboxamides, N-morpholinecarboxamide,N-benzylcarboxamide, N-thiomorpholinocarboxamide,N-picolinoylcarboxamide, O--X, CH₂ -(CH₂)_(p) --X, O--(CH₂)_(p) --X,(CH₂)_(p) --O--X, and CH═CH--X;

wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl,quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl,2-thienyl, 3-thienyl, or pyrimidyl; wherein p is 0-2;

wherein Q' and A are independently hydrogen, Ar, (C₁ -C₁₀)-straight orbranched alkyl, (C₂ -C₁₀)-straight or branched alkenyl or alkynyl, (C₅-C₇)cycloalkyl substituted-straight (C₁ -C₆)-straight or branched alkyl,(C₂ -C₆)-straight or branched alkenyl or alkynyl, (C₅ -C₇)-cycloalkenylsubstituted (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight orbranched alkenyl or alkynyl, or Ar substituted (C₁ -C₆)-straight orbranched alkyl, (C₂ -C₆)-straight or branched alkenyl or alkynylwherein, in each case, any one of the CH₂ groups of said alkyl, alkenylor alkynyl chains may be optionally replaced by a heteroatom selectedfrom the group consisting of O, S, SO, SO₂ and NR, wherein R is selectedfrom the group consisting of hydrogen, (C₁ -C₄)-straight or branchedalkyl, (C₂ -C₄)-straight or branched alkenyl or alkynyl, and (C₁-C₄)-bridging alkyl wherein a bridge is formed between the nitrogen anda carbon atom of said heteroatom-containing chain to form a ring, andwherein said ring is optionally fused to an Ar group; or ##STR3##wherein G' is hydrogen, (C₁ -C₆)-straight or branched alkyl or (C₂-C₆)-straight or branched alkenyl or alkynyl.

Another embodiment of this invention are compounds of formula I whereinZ is --(CH₂)_(m) --C(H)Q'A.

A preferred embodiment are compounds of formula I wherein J and K aretaken together to form a piperidine ring; the stereochemistry at carbon1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is3-phenylpropyl; and A is 3-(3-pyridyl)propyl.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a pyrrolidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is3-phenylpropyl; and A is 3-(3-pyridyl)propyl.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a piperidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' isphenyl; and A is 2-phenylethyl.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a pyrrolidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' isphenyl; and A is 2-phenylethyl.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a piperidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; and Q'and A are both (C₁ -C₄)-straight chain alkyls substituted at theterminal end with a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a pyrrolidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; and Q'and A are both (C₁ -C₄)-straight chain alkyls substituted at theterminal end with a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a piperidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is a(C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar; and A is a (C₁-C₄)-straight chain alkyl substituted at the terminal end with a (C₅-C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.

Another preferred embodiment are compounds of formula I wherein J and Kare taken together to form a pyrrolidine ring; the stereochemistry atcarbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is a(C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar; and A is a (C₁-C₄)-straight chain alkyl substituted at the terminal end with a (C₅-C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.

Another aspect of the present invention provides for a pharmaceuticalcomposition which comprises as an active ingredient an amount of acompound of formula I, or a pharmaceutically acceptable salt thereof,effective for stimulating neurite growth in nerve cells, and one or morepharmaceutically acceptable carriers, excipients or diluents thereof.

Another aspect of the present invention provides for a method forstimulating neurite growth in nerve cells comprising the step ofcontacting said nerve cells with a composition comprising a neurotrophicamount of a compound of formula I with affinity for an FK-506 bindingprotein.

Another aspect of the present invention provides for a method forstimulating neurite growth in nerve cells comprising the step ofcontacting said nerve cells with a composition comprising a neurotrophicamount of a compound of formula I with affinity for FKBP12.

GENERAL SUMMARY OF COMPOUND PREPARATION

The syntheses of the examples described in Table 1 was carried out usingone of the methods described below that are commonly employed in peptidechemistry (see M. Bodanszky and A. Bodanszky, "The Practice of PeptideSynthesis," Springer-Verlag, Berlin (1984)):

A) An acylation reaction involving p-methylthiophenolic ester ofα,α-difluoro-3,4,5-trimethoxyphenylacetic acid with appropriate prolylor pipecolate ester in dimethylformamide (DMF) in the presence ofdiisopropylethylamine. ##STR4## B) Acylation of proline or pipecolicacid with the p-methylthiophenolic ester ofα,α-difluoro-3,4,5-trimethoxyphenylacetic acid, followed byesterification of the resulting acid with the appropriate alcohol usinga water soluble carbodiimide coupling reagent in acetonitrile. ##STR5##C) Schotten-Baumann reaction of in situ generatedα,α-difluoro-3,4,5-trimethoxyphenylacetyl chloride with the appropriateprolyl or pipecolate ester. ##STR6## D) Peptide coupling usingcarbodiimide or a mixed anhydride approach were also used in some cases.##STR7##

The α,α-difluoro-3,4,5-trimethoxyphenylacetic acid or itsp-methylthiophenolic ester required for the above three approaches weresynthesized by fluorination of the parent keto compound withdiethylaminosulfurtrifluoride. In the case of the fluorination of3,4,5-trimethoxyphenyl-α-oxoacetic acid, the correspondingN,N-diethylamide was also obtained. This N,N-diethylamide could beeasily converted to the desired acid by alkaline hydrolysis. ##STR8##

The α,α-difluoro-3,4,5-trimethoxyphenylacetic acid was converted to thecorresponding acid chloride using oxalyl chloride and catalyticdimethylformamide in methylene chloride. ##STR9##

PREPARATION OF REAGENTS General

¹ H NMR spectra in deuterated chloroform were run on a Bruker AC-300 ora Varian Gemini 300 spectrometer and chemical shifts were reported inppm (δ) with reference to tetramethylsilane. All evaporations werecarried out on a rotary evaporator under reduced pressure. Magnesiumsulfate was used for drying the organic layer after extractive work up.LC-MS analysis were carried out on a Shimadzu instrument using either ofthe following two systems: System 1 consists of a PHX-LUNA C18 column(4.6×30 mm) employing a 4 min linear gradient of 20% to 100% solvent B:A(solvent A: 10% methanol, 90% water, 0.1% trifluoroacetic acid; solventB: 90% methanol, 10% water, 0.1% trifluoroacetic acid) with the UVdetector set at 220 nm. System 2 consists of a YMC C18 column (4.6×50mm) employing a 4 or 8 min linear gradient of 0% to 100% solvent B:Awith other conditions as described above for system 1. The water solublecarbodiimides used were either the hydrochloride salt or the methiodideof 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Abbreviationsused were in accordance with the guidelines provided by the AmericanChemical Society for their publications.

p-(Methylthio)phenolic ester of 3,4,5-trimethoxyphenyl-α-oxoacetic acid

To a stirred solution of 3,4,5-trimethoxyphenyl-α-oxoacetic acid (12.0g, 49.9 mmol) in anhydrous acetonitrile (150 mL) at ambient temperaturewas added 4-(methylthio)-phenol (8.40 g, 59.9 mmol),dicyclohexylcarbodiimide (DCC) (15.4 g, 74.9 mmol) and4-dimethylaminopyridine (0.428 g, 3.50 mmol) under nitrogen. Thereaction mixture was stirred for 8 h, then cooled to 0° C. in an icebath and 1M solution of oxalic acid in acetonitrile was added. Theprecipitated dicyclohexylurea was removed by filtration. The filtratewas diluted with ethyl acetate (400 mL) and the organic layer was washedwith water (3×200 mL), brine (200 mL) and dried. The solvent wasevaporated to give a pale yellow solid which was recrystallized from2-propanol to give the pure ester (11.0 g, 61% yield). MS: M+H =363. ¹H-NMR: 7.41 (s, 2H), 7.35 (d, J =8.7 Hz, H₂ & H₆, 2H), 7.21 (d, J=8.7Hz, H₃ & H₅, 2H), 3.99 (s, 3H), 3.94 (s, 6H), 2.52 (s, 3H).

p-(Methylthio)phenolic ester ofα,α-difluoro-3,4,5-trimethoxyphenylacetic acid

To a stirred solution of the p-(methylthio)phenolic ester of3,4,5-trimethoxyphenyl-α-oxoacetic acid (1.00 g, 2.76 mmol) in anhydrousmethylene chloride (10 mL) at room temperature was addeddiethylaminosulfurtrifluoride (DAST) (4.44 g, 27.6 mmol) under nitrogen.The reaction mixture was stirred overnight. It was then cooled in an icebath and excess DAST was quenched by dropwise addition of water. Ethylacetate (150 mL) was then added and the organic layer was washedrepeatedly with water until the pH of the aqueous layer was neutral. Theorganic layer was then washed with brine (50 mL), dried, and the solventevaporated to afford the title compound (0.961 g, 2.50 mmol, 91%) as abrown solid. ¹ H-NMR: 7.27 (d, J=8.7 Hz, H₂ & H₆, 2H), 7.04 (d, J=8.8Hz, H₃ & H₅, 2H), 6.92 (s, 2H), 3.92 (s, 6H), 3.91 (s, 3H), 2.48 (s,3H).

α,α-Difluoro-3,4,5-trimethoxyphenylacetic acid

To a stirred solution of 3,4,5-trimethoxyphenyl-α-oxoacetic acid (3.81g, 15.8 mmol) in anhydrous methylene chloride (30 mL) at roomtemperature was added DAST (20.4 g, 127 mmol) under nitrogen and themixture was stirred overnight. The mixture was then cooled in an icebath and excess DAST was quenched by dropwise addition of water. Ethylacetate (300 mL) was added and the organic layer was washed withsaturated aqueous sodium bicarbonate (2×100 mL) followed by water (100mL). The residue obtained after drying and evaporation was purified bysilica gel chromatography, eluting with hexane/ethyl acetate (9:1 to7:3), to give the N,N-diethylamide derivative (2.10 g, 6.62 mmol, 42%)as a pale yellow solid. ¹ H-NMR: 6.77 (s, 2H), 3.88 (s, 9H), 3.45 (q,J=7.0 Hz, 2H), 3.25 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.0 Hz, 3H), 1.10 (t,J=6.9 Hz, 3H). Bicarbonate washing after acidification and extractivework up with ethylacetate gave the crude title compound. Purification byreversed phase column (C18) chromatograhy eluting withwater/methanol/trifluoroacetic acid (69.9:30:0.1) gave the pure difluoroacid (0.616 g, 2.34 mmol, 15%) as a white solid. ¹ H-NMR: 6.85 (s, 2H),3.90 (s, 6H), 3.89 (s, 3H). Anal. C: 50.59, H: 4.72, F: 14.24 (found),C: 50.39, H: 4.61, F: 14.49 (calcd). The N,N-diethylamide (2.00 g, 6.30mmol) obtained above was hydrolyzed to the title acid by heating asolution in ethanol (5 mL) with 10% sodium hydroxide (13 mL) at refluxfor 4 h. Acidification followed by extractive work up with ethyl acetategave the crude acid which was purified as described above to give 1.51 gof the title compound as a white solid.

α,α-Difluoro-3,4,5-trimethoxyphenylacetylchloride

A stirred solution of α,α-difluoro-3,4,5-trimethoxyphenylacetic acid(1.50 g, 6.63 mmol) in anhydrous methylene chloride (20 mL) was treatedwith oxalyl chloride (2.52 g, 19.8 mmol) and 1 drop ofdimethylformamide. After vigorous effervescence ceased, the reactionmixture was stirred for 3 h. The solvents were evaporated and traces ofoxalyl chloride were removed by repeated evaporation with anhydrousmethylene chloride to give the acid chloride (1.61 g, 99% yield) as adark yellow solid.

EXAMPLE 1 ##STR10##

A suspension of N-Boc-L-proline (6.04 g, 28.0 mmol), 3-phenylpropanol(4.58 g, 33.6 mmol), DCC (8.68 g, 42.0 mmol), and4-dimethylaminopyridine (0.210 g, 1.72 mmol) in anhydrous ether (60 mL)was stirred under nitrogen for 8 h. Water (200 mL) was added and themixture was extracted with ethyl acetate (3×200 mL). The organic layerwas separated and washed with water (2×100 mL), brine (2×100 mL), driedand evaporated. Purification of the residue by silica gel chromatographyeluting with hexane/ethyl acetate (7:3 to 7:3) gave the purephenylpropyl ester (7.62 g, 81%) as a colorless oil. MS: M+H=334. ¹ HNMR: 7.26 (m, 2H), 7.17 (m, 3H), 4.31 & 4.21 (dd, J=8.1, 3.2 Hz, 1H),4.09 (m, 2H), 3.59-3.32 (m, 2H), 2.64 (t, J=8.9 Hz, 2H), 2.19 (m, 1H),1.91 (m, 5H), 1.42 (s, 4H), 1.39 (s, 6H). A portion of this material(0.393 g, 1.18 mmol), in methylene chloride (8 mL) was treated withtrifluoroacetic acid (0.13 mL). After 1 h volatiles were evaporated anda solution of the resulting trifluoroacetate salt in dimethylformamide(12 mL) was combined with p-methylthiophenolate ester of3,4,5-trimethoxy-α,α-difluorophenyl acetic acid (0.428 g, 1.18 mmol) anddiisopropylethylamine (0.152 g, 1.18 mmol). The solution was stirred for18 h, and then diluted with ethyl acetate (100 mL), washed with water(50 mL), and dried. The solvent was removed by evaporation. The residuewas purified by silica gel chromatography, eluting with hexane/ethylacetate (9:1 to 4:1) to give the product (0.360 g, 0.755 mmol, 64%) as abrown oil. (M+H)=478. ¹ H NMR: 7.25 (m, 2H), 7.17 (m, 3H), 6.87 (s, 2H),4.57 (m, 1H), 4.10 (m, 2H), 3.87 (s, 6H), 3.85 (s, 3H), 3.57 (m, 2H),2.68 (t, J=7.5 Hz, 2H), 2.16 (m, 1H), 1.96 (m, 5H).

EXAMPLE 2 ##STR11##

Esterification of N-Boc-L-proline (1.01 g, 4.60 mmol) with3-(3'-pyridyl)propan-1-ol (0.772 g, 5.60 mmol) was carried out using DCC(1.45 g, 7.00 mmol) and 4-dimethylaminopyridine (0.102 g, 0.834 mmol) inanhydrous ether (25 mL). Work up was carried out as described above forexample 1. Purification by silica gel chromatography, eluting withhexane/ethyl acetate (7:3 to 3:7) gave the N-Boc-prolylester of3-(3'-pyridyl)propan-1-ol (1.34 g, 4.00 mmol, 87%) as a colorless oil.MS: M+H=335. ¹ H-NMR: 8.42 (m, 2H), 7.50 (m, 1H), 7.20 (m, 1H), 4.36 &4.22 (dd, J=8.0, 3.0 Hz, 1H, rotamers), 4.17 (m, 2H), 3.49 (m, 2H), 2.70(t, J=10.0 Hz, 2H), 2.20 (m, 1H), 1.91 (m, 5H), 1.43 (s, 4.5H), 1.39 (s,4.5H). The N-Boc-prolylester of 3-(3'-pyridyl)propan-1-ol (0.271 g,0.811 mmol), was deprotected and coupled with the p-methylthiophenolateester of 3,4,5-trimethoxy-α,α-difluorophenyl acetic acid (0.312 g, 0.811mmol), diisopropylethylamine (0.104 g, 0.811 mmol) in dimethylformamide(20 mL) as described in example 1. The crude product was partitionedbetween ethyl acetate (200 mL) and 1M hydrochloric acid (2×25 mL). Theaqueous layer was basified with sodium bicarbonate and extracted withethyl acetate (3×100 mL). The solution was evaporated after washing withwater and drying. Purification of the residue by silica gelchromatography, eluting with chloroform/methanol (99.3:0.7) provided thetitle compound (0.331 g, 0.692 mmol, 85%) as pale brown oil. M+H=479. ¹H-NMR: 8.38 (m, 2H), 7.45 (m, 1H), 7.18 (m, 1H), 6.83 (s, 2H), 4.57 &4.53 (dd, J=8.5, 3.2 Hz, 1H, rotamers), 4.17 (m, 1H), 4.06 (m, 1H), 3.83(s, 6H), 3.81 (s, 3H), 3.53 (m, 2H), 2.66 (t, J=7.6 Hz, 2H), 2.12 (m,1H), 1.88 (m, 5H).

EXAMPLE 3 ##STR12##

The coupling of L-proline with the p-(methylthio)phenolic ester of(α,α-difluoro-3,4,5-trimethoxyphenylacetic acid was carried out asdescribed above for example 2. Thetrimethoxydifluorophenylacetamidoproline derivative was obtained in 89%yield after purification by silica gel chromatography, eluting withmethylene chloride/ethyl acetate/acetic acid (70:27.5:2.5). M+H=360. ¹H-NMR: 8.51 (br, OH), 6.88 (s, 2H), 4.65 (m, 1H), 3.89 (s, 9H), 3.55 (m,2H), 2.20 (m, 2H), 1.98 (m, 2H). LC-MS: System 1, t_(R) =5.2 min. Watersoluble carbodiimide (EDC hydrochloride, 0.318 g, 1.66 mmol) mediatedesterification of the intermediate acid (0.400 g, 1.11 mmol) with1-phenyl-7-(3'-pyridyl)-heptan-4-ol (0.358 g, 1.33 mmol), in thepresence of a catalytic amount of dimethylaminopyridine (0.101 g, 0.830mmol) in acetonitrile (25 mL) gave, after extractive work up with ethylacetate and water, the crude product. Purification by silica gelchromatography gave the title compound (0.425 g, 0.695 mmol, 63%) as ayellow oil. MS: M+H=611. ¹ H-NMR: 8.36 (m, 2H), 7.58-7.39 (m, 1H),7.22-7.07 (m, 6H), 6.80 (d, J=3.1 Hz, 2H), 4.88 (m, 1H), 4.48 (m, 1H),3.79 (m, 9H), 3.44 (m, 2H), 2.54 (m, 4H), 2.08 (m, 1H), 1.83 (m, 2H),1.52 (m, 9H). LC-MS: System 2 (8 min gradient), t_(R) for thediastereomers was 6.9 and 7.2 min.

EXAMPLE 4 ##STR13##

N-Boc-L-pipecolic acid (0.280 g, 1.22 mmol) was esterified with1-phenyl-7-(3'-pyridyl)-heptan-4-ol (0.394 g, 1.46 mmol) employing EDChydrochloride (0.350 g, 1.83 mmol) and 4-dimethylaminopyridine (0.081 g,0.663 mmol) in acetonitrile (25 mL). Purification by silica gelchromatography, eluting with chloroform/methanol (100:0 to 99:1), gavethe pure 1-phenyl-7-(3'-pyridyl)-heptan-4-ol ester of N-Boc-pipecolicacid in 85% yield (0.498 g) as a colorless oil. MS: M+H=481. LC-MS:System 2 (4 min gradient), t_(R) =3.8 min. A portion of this N-Boc ester(0.369 g, 0.768 mmol) was deprotected as described in example 1 withtrifluoroacetic acid. The crude product was then coupled withα,α-difluoro-3,4,5-trimethoxyphenylacetic acid (0.241 g, 0.921 mmol),using EDC hydrochloride (0.220 g, 1.15 mmol) and 4-dimethylaminopyridine(0.101 g, 0.826 mmol) in acetonitrile (25 mL). After extractive work upas described in example 1, the product was purified by silica gelchromatography, eluting with hexane/ethyl acetate (4:1 to 1:1), to givethe title compound (0.624 g, 1.05 mmol, 78%) as a pale yellow oil. MS:M+H=625. ¹ H-NMR: 8.38-8.34 (m, 2H), 7.75-7.00 (m, 7H), 6.76-6.63 (m &s, 2H), 5.25-4.10 (4×m, 2H), 3.80-3.50 (m, 1OH), 3.00-2.85 (m, 1H), 2.52(m, 2H), 2.25-1.00 (4×m, 16H). LC-MS: System 2 (4 min gradient), t_(R),for the diastereomers=3.6 and 3.8 min. Anal. C₃₅ H₄₂ N₂ O₆ F₂, C=67.40,H=6.85, N=4.23, F=5.86 (found) C=67.29, H=6.78, N=4.48, F=6.08 (calcd.).

EXAMPLE 5 ##STR14##

N-Boc-L-proline (2.01 g, 9.29 mmol) was esterified with1,1-dimethyl-3-phenyl propanol (1.83 g, 11.1 mmol) using EDC methiodide(4.14 g, 13.9 mmol) and 4-dimethylaminopyridine (0.100 g, 0.815 mmol) inanhydrous acetonitrile (30 mL) as described in example 4. Followingaqueous/organic extractive work up, purification by silica gelchromatography, eluting with hexane:ethyl acetate (95:5 to 80:20), gavepure 1,1-dimethyl-3-phenylpropyl ester (1.13 g, 3.13 mmol, 34%) as acolorless oil. MS: M+H=362. ¹ H-NMR: 7.29 (m, 2H), 7.18 (m, 3H), 4.23 &4.17 (dd, J=8.9 & 3.4 Hz, 1H), 3.60-3.35 (m, 2H), 2.65 (m, 2H),2.27-1.83 (br m, 6H), 1.46 (s, 4H), 1.44 (s, 6H). A portion of thisBoc-protected ester (0.689g, 1.90 mmol) was deprotected withtrifluoroacetic acid as described in example 1 and acylated with thep-(methylthio)phenolic ester ofα,α-difluoro-3,4,5-trimethoxyphenylacetic acid (0.533 g, 1.39 mmol) inthe presence of diisopropylethylamine (0.246 g, 1.90 mmol) indimethylformamide (10 mL). After extractive work up using ethyl acetate,the crude product was purified by silica gel chromatography, elutingwith hexane/ethyl acetate (9:1 to 7:3), to give the title compound(0.350 g, 0.693 mmol, 36%) as a pale brown oil. MS: M+H=506. ¹ H-NMR:7.27 (m, 2H), 7.16 (m, 3H), 6.90 (s, 2H), 4.52 (m, 1H), 3.86 (s, 9H),3.57 (m, 2H), 2.75-2.50 (m, 2H), 2.20-1.87 (m, 6H), 1.49 (d, J=2.7 Hz,6H).

EXAMPLE 6 ##STR15##

The coupling of L-proline with the p-(methylthio)phenolic ester ofα,α-difluoro-3,4,5-trimethoxyphenylacetic acid was carried out asdescribed in example 5. The intermediatetrimethoxydifluorophenylacetamidoproline derivative (0.455 g, 1.26 mmol)was esterified with 1,3-diphenylpropanol (0.325 g, 1.51 mmol) using EDChydrochloride (0.362 g, 1.90 mmol) and 4-dimethylaminopyridine (0.081g,0.656 mmol) in anhydrous acetonitrile (20 mL). Following extractive workup, purification by silica gel chromatography, eluting with hexane/ethylacetate (9:1 to 7:3), gave the desired compound (0.182 g, 0.328 mmol,26%) as a colorless oil. MS: M+H=554. ¹ H-NMR: 7.31 (m, 7H), 7.20 (m,3H), 6.81 (s, 2H), 5.74 (m, 1H), 4.71 (m, 1H), 3.88 (d, J=7.1 Hz, 3H),3.78 (d, J=5.5 Hz, 6H), 3.59 (m, 2H), 2.63 (m, 2H), 2.33-1.85 (m, 6H).LC-MS: System 2 (8 min gradient), t_(R) =8.2 min.

EXAMPLE 7 ##STR16##

N-Boc pipecolic acid (0.345 mg, 1.5 mmol) was esterified as described inexample 5 with 1,3-diphenyl-1-propanol to obtain the diphenylpropylester in 45% yield. MS: M+H=424. LC-MS: System 2 (4 min gradient), t_(R)=4.8 min. A portion of this N-Boc-protected ester (270 mg, 0.64 mmol)was deprotected with trifluoroacetic acid as described in example 1. Theresulting trifluoroacetate salt in dichloromethane (4 mL) was acylatedwith freshly prepared α,α-difluoro-3,4,5-trimethoxyphenylacetyl chloride(201 mg, 1.2 equiv). After 15 h, the solvent was evaporated and theresidue was purified by chromatography on reversed phase (C18) silicagel, eluting first with methanol/0.1% trifluoroacetic acid in water(7:3). This was followed by silica gel chromatography of the combinedfractions, eluting with ethyl acetate/hexane (3:7), to give a colorlessoil (183 mg, 50% yield). MS: M+H=568. ¹ H-NMR: 7.38-7.15 (m, 10H),6.85-6.70 (set of 4 s, 2H), 5.78-5.73 (m, 1H), 5.42-4.60 (2 sets of m,1H), 4.07-3.67 (m, 10H), 2.97-2.85 (m, 1H), 2.72-2.53 (m, 2H), 2.42-2.08(m, 3H), 1.85-1.00 (m, 5H). LC-MS: System 2 (4 min gradient), t_(R) =4.6min. Anal. C₃₂ H₃₅ NO₆ F₂.0.25 CH₃ COOC₂ H₅, C=67.10, H=6.56, N=2.13,F=6.85 (found), C=67.22, H=6.32, N=2.38, F=6.44 (calcd.).

EXAMPLE 8 ##STR17##

The coupling of L-proline with the p-(methylthio)phenolic ester ofα,α-difluoro-3,4,5-trimethoxyphenylacetic acid was carried out asdescribed for example 5. The intermediatetimethoxyphenyldifluoroacetamidoproline derivative (0.455 g, 1.26 mmol)was esterified with 3-(3,4,5-trimethoxyphenyl)propan-1-ol as describedin example 6 to give the trimethoxyphenylpropyl ester in 42% as acolorless oil. MS: M+H=568. ¹ H-NMR: 6.89 (s, 2H), 6.43 (s, 2H), 4.61(m, 1H), 4.22 (m, 1H), 4.10 (m, 1H), 3.88 (m, 9H), 3.84 (m, 9H), 3.57(m, 2H), 2.67 (m, 2H), 2.20 (m, 1H), 1.96 (m, 5H). LC-MS: System 2 (8min gradient), t_(R) =7.0 min.

EXAMPLE 9 ##STR18##

The synthesis of this compound was carried out as as described forexample 7. N-Boc pipecolic acid (345 mg, 1.5 mmol) was esterified with3-(3,4,5-trimethoxyphenyl)propan-1-ol to obtain thetrimethoxyphenylpropyl ester in 52% yield. MS: M+H=438. LC-MS: System 2(4 min gradient), t_(R) =4.2 min. A portion of this Boc-protected ester(325 mg, 0.744 mmol) was deprotected and acylated as described inexample 7 with α,α-difluoro-3,4,5-trimethoxyphenylacetyl chloride toobtain 183 mg (42%) of the desired compound. MS: M+H=582. ¹ H-NMR:6.84-6.38 (set of 4 s, 4H), 5.42-4.55 (2×m, 1H), 4.24-3.75 (m, 21H),3.04-2.96 (m, 1H), 2.67-2.54 (m, 2H), 2.36-2.10 (m, 1H), 2.03-1.15 (m,7H). LC-MS: System 2 (4 min gradient), t_(R) =4.0 min. Anal. C₂₉ H₃₇ F₂NO₉.0.25 CH₃ COOC₂ H₅, C=59.66, H=6.63, N=2.24, F=6.70 (found), C=59.69,H=6.51, N=2.32, F=6.29 (calcd.).

EXAMPLE 10 FKBP12 Rotamase Inhibition Assay

The rotamase activity of FKBP-12 was measured by an adaptation of theassay described by Kofron et al. (Biochemistry, 30, pp. 6127-6134(1991)). The assay was carried out at 4° C. with 1 mg chymotrypsin/mL ofassay solution with succinyl-Ala-Leu-Pro-Phe-p-nitroanilide as thesubstrate. Chymotrypsin rapidly hydrolyzes the peptide bond on theC-terminal side of the Phe of the trans form of the peptide and releasesthe chromogenic p-nitroaniline. The rate of the reaction is controlledby the rate of conversion of the cis form of the peptide to thetransform, the reaction catalyzed by FKBP12. The apparent K_(i) valuesof compounds of formula I for inhibition of the rotamase activity weredetermined by measuring decreases in the first order rate constant ofthe reaction catalyzed by FKBP12 as a function of the concentrations ofthe compounds described herein. K_(i) is the concentration of thecompound that causes 50% inhibition of rotamase activity which isindicative of neurite outgrowth activity. The results are presented inTable I.

EXAMPLE 11 Assay of Neurite Outgrowth in PC12 Cell Cultures

PC-12A rat pheochromocytoma cells are maintained in Dulbecco's modifiedEagle's medium (DMEM) supplemented with 10% fetal calf serum and 5% calfserum at 37° C. and 5% CO₂. Cells to be assayed are plated at 10⁴ perwell of a 24 well plate an allowed to attach for 4-18 h.

The medium is then replaced with DMEM plus 0.1% BSA (bovine serumalbumin), submaximal concentrations of NGF (nerve growth factor) (asdetermined by neurite outgrowth assay), and varying concentrations ofthe FKBP12 binding compound (0.1 nM-10 μM) in a final concentration of0.25% DMSO (dimethylsulfoxide). Control cultures are treated with NGF inthe absence of the FKBP12 binding compound. After 72 hours, cultures arefixed with 4% formalin in PBS (phosphate buffered saline), stained withCommassie Blue, and approximately 200 cells are counted in random fieldsof each well. Cells with neurites longer than one cell diameter arecounted as a percentage of total number of cells.

The FKBP12 binding compounds of formula I utilized in this inventioncause a significant increase in neurite outgrowth over control cultures.

Additionally, compounds of this invention may also show benefit asreversers of multidrug resistance (MDR) in cancer chemotherapy and asagents for the treatment of HIV infection. Nonimmunosuppressivecompounds possessing the structural elements of the FKBP12 bindingportion of FK506 have shown utility in reversing P-glycoprotein mediatedMDR (U. A. Germann, et al., Anti-Cancer Drugs, 8, pp. 125-140 (1997)).In addition, there has been no direct correlation shown between rotamaseinhibitory activity and MDR reversing activity (J. R. Hauske, et al.,Bioorg. Med. Chem. Lett., 4, pp. 2097-2102 (1994)). In the area of HIVinfection, it is known that immunophilins, including the FK506 bindingproteins (FKBPs), are involved in facilitating binding of the HIVenvelope protein gp120 to host CD4 receptors (M. M. Endrich, et al.,Eur. J. Biochem., 252, pp. 441-446(1998)), and that FK506 inhibits thegrowth of HIV-infected cells (A. Kapas, et al., Proc. Natl. Acad. SciUSA, 89, pp. 8351-8355 (1992)).

                  TABLE 1                                                         ______________________________________                                        Rotamase inhibition data with selected examples                                ##STR19##                                                                                                          Percent                                                                 K.sub.i                                                                             Inhibition                              Example                                                                              n     R                  (nM)  at 10 μM                             ______________________________________                                        1      1     3-phenylpropyl     1300  97                                      2      1     3-(3-pyridyl)propyl                                                                              877   97                                      3      1     4-[7-(3-pyridyl)-1-phenylheptyl]                                                                 104   97                                      4      2     4-[7-(3-pyridyl)-1-phenylheptyl]                                                                  19   98                                      5      1     3-(1-phenyl-3-methylbutyl)                                                                             70                                      6      1     1-(1,3-diphenylpropyl)                                                                            83   100                                     7      2     1-(1,3-diphenylpropyl)   94                                      8      1     3-(3',4',5'-trimethoxyphenyl)propyl                                                                    38                                      9      2     3-(3',4',5'-trimethoxyphenyl)propyl                                                              109   99                                      ______________________________________                                    

If pharmaceutically acceptable salts of the compounds of formula I areused, those salts are preferably derived from inorganic or organic acidsand bases. Included among such acid salts are the following: acetate,aspartate, bisulfate, butyrate, citrate, fumarate, hydrochloride,hydrobromide, hydroiodide, lactate, maleate, oxalate, persulfate,propionate, succinate, tartrate. Base salts include ammonium salts,alkali metal salts, such as sodium and potassium salts, alkaline earthmetal salts, such as calcium and magnesium salts, salts with organicbases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and saltswith amino acids such as arginine, lysine, and so forth.

Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, and the judgment of the treating physician and theseverity of the particular disease being treated. The amount of compoundof formula I will also depend upon the particular FKBP12 bindingcompound in the composition.

The amount of compound of formula I utilized in these methods is betweenabout 0.01 and 100 mg/kg body weight/day.

What is claimed is:
 1. A compound having the formula (I): ##STR20## and pharmaceutically acceptable salts thereof: wherein W is CH₂, O, NH, or N--(C₁ -C₄)-alkyl;wherein J is hydrogen, (C₁ -C₄)-alkyl or benzyl; wherein K is (C₁ -C₄)-straight or branched alkyl, benzyl or cyclohexylmethyl, or wherein J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of O, S, SO, and SO₂ ; wherein the stereochemistry at carbon position 1 is R or S; wherein Z is Q or --(CH₂)_(m) --C(H)Q'A; wherein m is 0-3; wherein Q is hydrogen, CHL-Ar, (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl, (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl, Ar substituted (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl or ##STR21## wherein L and G are independently hydrogen, (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl; wherein T is Ar or substituted cyclohexyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O--(C₁ -C₄)-alkyl or O--(C₂ -C₄)-alkenyl and carbonyl; wherein D is (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl, (C₅ -C₇)-cycloalkyl or (C₅ -C₇)-cycloalkenyl substituted with (C₁ -C₄)-straight or branched alkyl or (C₂ -C₄)-straight or branched alkenyl, O--(C₁ -C₄)-straight or branched alkyl, O--(C₂ -C₄)-straight or branched alkenyl, [(C₁ -C₄)-alkyl or (C₂ -C₄)-alkenyl]-Ar or Ar; wherein Ar is a carbocyclic aromatic group selected from the group consisiting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl, O--[(C₁ -C₄)-straight or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, N-[(C₁ -C₅)-straight or branched alkyl or (C₂ -C₅)-straight or branched alkenyl] carboxamides, N,N-di-[(C₁ -C₅)-straight or branched alkyl or (C₂ -C₅)-straight or branched alkenyl] carboxamides, N-benzylcarboxamide, O--X, CH₂ --(CH₂)_(p) --X, O--(CH₂)_(p) --X, (CH₂)_(p) --O--X, and CH═CH--X; wherein X is 4-methoxyphenyl; wherein p is 0-2; wherein Q' and A are independently hydrogen, Ar, (C₁ -C₁₀)-straight or branched alkyl, (C₂ -C₁₀)-straight or branched alkenyl or alkynyl, (C₅ -C₇)cycloalkyl substituted-straight (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl or alkynyl, (C₅ -C₇)-cycloalkenyl substituted (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl or alkynyl, or Ar substituted (C₁ -C₆)-straight or branched alkyl, (C₂ -C₆)-straight or branched alkenyl or alkynyl wherein, in each case, any one of the CH₂ groups of said alkyl, alkenyl or alkynyl chains may be optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO₂ and NR, wherein R is selected from the group consisting of hydrogen, (C₁ -C₄)-straight or branched alkyl, (C₂ -C₄)-straight or branched alkenyl or alkynyl, and (C₁ -C₄)-bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group; or ##STR22## wherein G' is hydrogen, (C₁ -C₆)-straight or branched alkyl or (C₂ -C₆)-straight or branched alkenyl or alkynyl.
 2. A compound of claim 1 wherein Z is --(CH₂)_(m) --C(H)Q'A.
 3. A compound of claim 2 wherein J and K are taken together to form a piperidine ring; the stereochemistry at carbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is phenyl; and A is 2-phenylethyl.
 4. A compound of claim 2 wherein J and K are taken together to form a pyrrolidine ring; the stereochemistry at carbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is phenyl; and A is 2-phenylethyl.
 5. A compound of claim 2 wherein J and K are taken together to form a piperidine ring; the stereochemistry at carbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; and Q' and A are both (C₁ -C₄)-straight chain alkyls substituted at the terminal end with a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.
 6. A compound of claim 2 wherein J and K are taken together to form a pyrrolidine ring; the stereochemistry at carbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; and Q' and A are both (C₁ -C₄)-straight chain alkyls substituted at the terminal end with a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.
 7. A compound of claim 2 wherein J and K are taken together to form a piperidine ring; the stereochemistry at carbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar; and A is a (C₁ -C₄)-straight chain alkyl substituted at the terminal end with a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.
 8. A compound of claim 2 wherein J and K are taken together to form a pyrrolidine ring; the stereochemistry at carbon 1 is S; W is oxygen; m is 0; D is 3,4,5-trimethoxyphenyl; Q' is a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar; and A is a (C₁ -C₄)-straight chain alkyl substituted at the terminal end with a (C₅ -C₇)-cycloalkyl, (C₅ -C₇)-cycloalkenyl or Ar.
 9. A pharmaceutical composition which comprises as an active ingredient an amount of a compound as claimed in any one of claims 1, 2, and 5 to 8, or a pharmaceutically acceptable salt thereof, effective for stimulating neurite growth in nerve cells, and one or more pharmaceutically acceptable carriers, excipients or diluents thereof.
 10. A method for stimulating neurite growth in nerve cells comprising the step of contacting said nerve cells with a composition comprising a neurotrophic amount of a compound with affinity for an FK-506 binding protein as claimed in any one of claims 1, 2 and 3-8.
 11. A method for stimulating neurite growth in nerve cells comprising the step of contacting said nerve cells with a composition comprising a neurotrophic amount of a compound with affinity for FKBP12 as claimed in any one of claims 1, 2 and 5-8. 